EP0161796A1 - Process for producing N-acylphenylalanines - Google Patents
Process for producing N-acylphenylalanines Download PDFInfo
- Publication number
- EP0161796A1 EP0161796A1 EP85302503A EP85302503A EP0161796A1 EP 0161796 A1 EP0161796 A1 EP 0161796A1 EP 85302503 A EP85302503 A EP 85302503A EP 85302503 A EP85302503 A EP 85302503A EP 0161796 A1 EP0161796 A1 EP 0161796A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- catalyst
- oxazolone
- group
- palladium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 37
- 239000003054 catalyst Substances 0.000 claims abstract description 51
- 230000009467 reduction Effects 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 20
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 230000007062 hydrolysis Effects 0.000 claims abstract description 10
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 9
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 6
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 238000006722 reduction reaction Methods 0.000 claims description 39
- -1 methylenedioxy group Chemical group 0.000 claims description 21
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims description 3
- 229910003446 platinum oxide Inorganic materials 0.000 claims description 3
- 108010011485 Aspartame Proteins 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Inorganic materials [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 150000008547 L-phenylalanines Chemical class 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 9
- VGNJAJPQOALEIK-UHFFFAOYSA-N 2-benzylidene-1,3-oxazol-5-one Chemical class N1=CC(=O)OC1=CC1=CC=CC=C1 VGNJAJPQOALEIK-UHFFFAOYSA-N 0.000 abstract 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 abstract 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- BWQBTJRPSDVWIR-UHFFFAOYSA-N 4-benzylidene-2-methyl-1,3-oxazol-5-one Chemical class O=C1OC(C)=NC1=CC1=CC=CC=C1 BWQBTJRPSDVWIR-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000007858 starting material Substances 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- CBQJSKKFNMDLON-JTQLQIEISA-N N-acetyl-L-phenylalanine Chemical compound CC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-JTQLQIEISA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910000510 noble metal Inorganic materials 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- ZCWRGPJCVOZVQG-UHFFFAOYSA-M sodium;2-acetamido-3-phenylprop-2-enoate Chemical compound [Na+].CC(=O)NC(C([O-])=O)=CC1=CC=CC=C1 ZCWRGPJCVOZVQG-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- NKETWAIWIDBDON-VIFPVBQESA-N (2s)-2-(n-prop-2-enoylanilino)propanoic acid Chemical compound OC(=O)[C@H](C)N(C(=O)C=C)C1=CC=CC=C1 NKETWAIWIDBDON-VIFPVBQESA-N 0.000 description 1
- XFHQGYBXSCRMNT-JTQLQIEISA-N (2s)-3-phenyl-2-(prop-2-enoylamino)propanoic acid Chemical class C=CC(=O)N[C@H](C(=O)O)CC1=CC=CC=C1 XFHQGYBXSCRMNT-JTQLQIEISA-N 0.000 description 1
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical class O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- MGAHWEWWFYOBNW-RVDMUPIBSA-N (4e)-4-[(4-methoxyphenyl)methylidene]-2-phenyl-1,3-oxazol-5-one Chemical compound C1=CC(OC)=CC=C1\C=C\1C(=O)OC(C=2C=CC=CC=2)=N/1 MGAHWEWWFYOBNW-RVDMUPIBSA-N 0.000 description 1
- XODAOBAZOQSFDS-JXMROGBWSA-N (e)-2-acetamido-3-phenylprop-2-enoic acid Chemical compound CC(=O)N\C(C(O)=O)=C\C1=CC=CC=C1 XODAOBAZOQSFDS-JXMROGBWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GXQWQJTWVARFQS-UHFFFAOYSA-N 2-benzamidoacetic acid Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1.OC(=O)CNC(=O)C1=CC=CC=C1 GXQWQJTWVARFQS-UHFFFAOYSA-N 0.000 description 1
- ABKZDDODHUYTAP-UHFFFAOYSA-N 2-methyl-4-[(3-phenoxyphenyl)methylidene]-1,3-oxazol-5-one Chemical compound O=C1OC(C)=NC1=CC1=CC=CC(OC=2C=CC=CC=2)=C1 ABKZDDODHUYTAP-UHFFFAOYSA-N 0.000 description 1
- DRSAXSPSSHVKSE-UHFFFAOYSA-N 2-methyl-4-[(4-methylphenyl)methylidene]-1,3-oxazol-5-one Chemical compound O=C1OC(C)=NC1=CC1=CC=C(C)C=C1 DRSAXSPSSHVKSE-UHFFFAOYSA-N 0.000 description 1
- YQFBCPLZOMNPEZ-UHFFFAOYSA-N 2-phenyl-4-[(4-propan-2-ylphenyl)methylidene]-1,3-oxazol-5-one Chemical compound C1=CC(C(C)C)=CC=C1C=C1C(=O)OC(C=2C=CC=CC=2)=N1 YQFBCPLZOMNPEZ-UHFFFAOYSA-N 0.000 description 1
- PXEBLRXMMZXMAM-UHFFFAOYSA-N 2-phenyl-4-[(4-propoxyphenyl)methylidene]-1,3-oxazol-5-one Chemical compound C1=CC(OCCC)=CC=C1C=C1C(=O)OC(C=2C=CC=CC=2)=N1 PXEBLRXMMZXMAM-UHFFFAOYSA-N 0.000 description 1
- XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical class OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 description 1
- YIPBMFCRAFHCPQ-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-ylmethylidene)-2-methyl-1,3-oxazol-5-one Chemical compound O=C1OC(C)=NC1=CC1=CC=C(OCO2)C2=C1 YIPBMFCRAFHCPQ-UHFFFAOYSA-N 0.000 description 1
- RKXHYEBOSSBZSH-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-ylmethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound N=1C(=CC=2C=C3OCOC3=CC=2)C(=O)OC=1C1=CC=CC=C1 RKXHYEBOSSBZSH-UHFFFAOYSA-N 0.000 description 1
- UZPKKAMGTDPZOO-UHFFFAOYSA-N 4-[(2,3-dimethoxyphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound COC1=CC=CC(C=C2C(OC(C)=N2)=O)=C1OC UZPKKAMGTDPZOO-UHFFFAOYSA-N 0.000 description 1
- XYASTVNLIUEYBR-UHFFFAOYSA-N 4-[(2,4-dimethoxyphenyl)methylidene]-2-phenyl-1,3-oxazol-5-one Chemical compound COC1=CC(OC)=CC=C1C=C1C(=O)OC(C=2C=CC=CC=2)=N1 XYASTVNLIUEYBR-UHFFFAOYSA-N 0.000 description 1
- FWLIOHZSWASSAO-UHFFFAOYSA-N 4-[(3,4-dichlorophenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound O=C1OC(C)=NC1=CC1=CC=C(Cl)C(Cl)=C1 FWLIOHZSWASSAO-UHFFFAOYSA-N 0.000 description 1
- MYUAUDNSRVTJCU-UHFFFAOYSA-N 4-[(3,4-dichlorophenyl)methylidene]-2-phenyl-1,3-oxazol-5-one Chemical compound C1=C(Cl)C(Cl)=CC=C1C=C1C(=O)OC(C=2C=CC=CC=2)=N1 MYUAUDNSRVTJCU-UHFFFAOYSA-N 0.000 description 1
- WJEFTWGOJUEFSA-UHFFFAOYSA-N 4-[(3,4-diethoxyphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound C1=C(OCC)C(OCC)=CC=C1C=C1C(=O)OC(C)=N1 WJEFTWGOJUEFSA-UHFFFAOYSA-N 0.000 description 1
- ABAKBSGPUNJZIZ-UHFFFAOYSA-N 4-[(3,4-dimethoxyphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound C1=C(OC)C(OC)=CC=C1C=C1C(=O)OC(C)=N1 ABAKBSGPUNJZIZ-UHFFFAOYSA-N 0.000 description 1
- RVBXMTLYWMJFHD-UHFFFAOYSA-N 4-[(3,5-dimethoxyphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound COC1=CC(OC)=CC(C=C2C(OC(C)=N2)=O)=C1 RVBXMTLYWMJFHD-UHFFFAOYSA-N 0.000 description 1
- LMLPPLSCDUSBPH-UHFFFAOYSA-N 4-[(3-phenoxyphenyl)methylidene]-2-phenyl-1,3-oxazol-5-one Chemical compound O=C1OC(C=2C=CC=CC=2)=NC1=CC(C=1)=CC=CC=1OC1=CC=CC=C1 LMLPPLSCDUSBPH-UHFFFAOYSA-N 0.000 description 1
- ZLPBQSSTXLDZNP-UHFFFAOYSA-N 4-[(4-butoxyphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound C1=CC(OCCCC)=CC=C1C=C1C(=O)OC(C)=N1 ZLPBQSSTXLDZNP-UHFFFAOYSA-N 0.000 description 1
- HQEZFNSMCPUHKL-UHFFFAOYSA-N 4-[(4-butylphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound C1=CC(CCCC)=CC=C1C=C1C(=O)OC(C)=N1 HQEZFNSMCPUHKL-UHFFFAOYSA-N 0.000 description 1
- NWYIDAQFRYQRFT-UHFFFAOYSA-N 4-[(4-chlorophenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound O=C1OC(C)=NC1=CC1=CC=C(Cl)C=C1 NWYIDAQFRYQRFT-UHFFFAOYSA-N 0.000 description 1
- YTJIBIRWVTXTST-UHFFFAOYSA-N 4-[(4-ethoxyphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound C1=CC(OCC)=CC=C1C=C1C(=O)OC(C)=N1 YTJIBIRWVTXTST-UHFFFAOYSA-N 0.000 description 1
- STTTYGNQDNTOOP-UHFFFAOYSA-N 4-[(4-ethylphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound C1=CC(CC)=CC=C1C=C1C(=O)OC(C)=N1 STTTYGNQDNTOOP-UHFFFAOYSA-N 0.000 description 1
- NRQHBNNTBIDSRK-UHFFFAOYSA-N 4-[(4-methoxyphenyl)methylidene]-2-methyl-1,3-oxazol-5-one Chemical compound C1=CC(OC)=CC=C1C=C1C(=O)OC(C)=N1 NRQHBNNTBIDSRK-UHFFFAOYSA-N 0.000 description 1
- IFRAFVGTPWYBBQ-UHFFFAOYSA-N 4-[(4-methylphenyl)methylidene]-2-phenyl-1,3-oxazol-5-one Chemical compound C1=CC(C)=CC=C1C=C1C(=O)OC(C=2C=CC=CC=2)=N1 IFRAFVGTPWYBBQ-UHFFFAOYSA-N 0.000 description 1
- VFDOKJVMHZUBTN-UHFFFAOYSA-N 4-benzylidene-2-phenyl-1,3-oxazol-5-one Chemical compound O=C1OC(C=2C=CC=CC=2)=NC1=CC1=CC=CC=C1 VFDOKJVMHZUBTN-UHFFFAOYSA-N 0.000 description 1
- 0 CC1(C2)*(CCC3)*3C2(*)CCC(*)CC1 Chemical compound CC1(C2)*(CCC3)*3C2(*)CCC(*)CC1 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DMGXTEIBZJZYKU-UHFFFAOYSA-N [2-acetyloxy-4-[(2-methyl-5-oxo-1,3-oxazol-4-ylidene)methyl]phenyl] acetate Chemical compound C1=C(OC(C)=O)C(OC(=O)C)=CC=C1C=C1C(=O)OC(C)=N1 DMGXTEIBZJZYKU-UHFFFAOYSA-N 0.000 description 1
- LKTIYBGKWLNKGK-UHFFFAOYSA-N [2-acetyloxy-4-[(5-oxo-2-phenyl-1,3-oxazol-4-ylidene)methyl]phenyl] acetate Chemical compound C1=C(OC(C)=O)C(OC(=O)C)=CC=C1C=C1C(=O)OC(C=2C=CC=CC=2)=N1 LKTIYBGKWLNKGK-UHFFFAOYSA-N 0.000 description 1
- IIFDOCUPPJXLMD-UHFFFAOYSA-N [4-[(2-methyl-5-oxo-1,3-oxazol-4-ylidene)methyl]phenyl] acetate Chemical compound C1=CC(OC(=O)C)=CC=C1C=C1C(=O)OC(C)=N1 IIFDOCUPPJXLMD-UHFFFAOYSA-N 0.000 description 1
- QEUQVGFKMXYPPU-UHFFFAOYSA-N [4-[(5-oxo-2-phenyl-1,3-oxazol-4-ylidene)methyl]phenyl] acetate Chemical compound C1=CC(OC(=O)C)=CC=C1C=C1C(=O)OC(C=2C=CC=CC=2)=N1 QEUQVGFKMXYPPU-UHFFFAOYSA-N 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 235000008729 phenylalanine Nutrition 0.000 description 1
- 150000002994 phenylalanines Chemical class 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
Definitions
- This invention relates to a process for producing substituted or unsubstituted N-acylphenylalanines.
- N-acylphenylalanines are important compounds as precursors of phenylalanines.
- unsubstituted N-acylphenylalanines are categorized as essential amino acids and are important compounds as precursors of L-phenylalanine which has come to be rapidly used as a starting material of an artificial sweetner "Aspartame".
- N-acetylphenylalanine readily undergoes asymmetric hydrolysis by the action of an enzyme acylase to form L-phenylalanine.
- N-acrylphenylalanines have generally been produced by the reduction of either 2-substituted-4-(substituted) benzylidene-5-oxazolones, which are produced relatively easily by a condensation reaction of an N-acylglycine and a benzaldehyde, or ⁇ -acylaminocinnamic acids which are hydrolysis products of said oxazolones.
- noble metals such as palladium or platinum have also come to be used frequently on an industrial scale as catalysts for use in catalytic reduction. This is because these catalysts are effective in relatively small amounts, are recovered easily because they are heterogeneous to various solvents, and eliminate environmental problems caused by disposal because they are regenerative. They are extremely expensive, however. These expensive noble metal catalysts are generally used repeatedly in industry by way of their recovery after completion of reaction.
- the present inventors have hydrolyzed 2-methyl-4-benzylidene-5-oxazolone with alkali in water and reduced catalytically the resultant of-acetylamino- cinnamic acid, without isolating it from the reaction solution, by adding a palladium or platinum reducing catalyst thereto to prepare N-acetylphenylalanine. It was then found that the catalyst recovered by filtration after the reduction was lowered in catalytic activity through use, thus requiring considerably longer times in effecting subsequent reductions compared with reductions performed with fresh catalyst. Finally, the noble metal catalyst lost its activity almost completely after several repeated uses thereof.
- the present invention provides a process for producing N-acylphenylalanines represented by the general formula (II): wherein R 4 and R 5 independently of one another are a hydrogen atom, an alkyl group having 1 - 4 carbon atoms, an alkoxy group having 1 - 4 carbon atoms, a halogen atom, a hydroxyl group or an aryloxy group, or in combination are the methylenedioxy group, and R 3 is a methyl or phenyl group, which process comprises hydrolyzing, with alkali, 2-substituted-4-(substituted) benzylidene-5-oxazolones represented by the general formula (I): wherein each R and R 2 independently of one another are a hydrogen atom, an alkyl group having 1 - 4 carbon atoms, an alkoxy group having 1 - 4 carbon atoms, a halogen atom, an acyloxy group or an aryloxy group, or adjoiningly to each other
- the time period required for the reduction can be remarkably shortened compared with the time required for reduction in an aqueous, strong alkaline solution. Moreover, there is such a great advantage in the present process that the catalyst recovered through filtration after the reduction can be used repeatedly without any additional treatment and without any observed decrease in its catalytic activity. A reduction using the catalyst recovered from a previous reduction may proceed at practically the same rate as in the case of a reduction performed using fresh catalyst.
- the starting material 2-substituted -4-(substituted) benzylidene-5-oxazolone
- the present process has advantages over a process wherein a N-acylaminocinnamic acid is reduced after it has been isolated from the reaction system; the advantages include the benelit-of process simplification and surprisingly improved overall yield.
- R 1 and R are univalent, they can be attached to any unoccupied position on the benzylidene ring. If R 1 and R 2 (and R 3 and R 4 ) are combined as the divalent methylenedioxy group, however, this group attaches to two adjoining positions of the benzylidene ring.
- the process of the present invention comprises two steps consisting of (A) treating a 2-substituted-4-(substituted) benzylidene-5-oxazolone represented by the general formula (I) with alkali to form a substituted or unsubstituted ⁇ -acylaminocinnamic acid and (B) reducing catalytically the resultant ⁇ -acylaminocinnamic acid without isolating it from the reaction system.
- 2-substituted-4-(substituted)benzylidene-5-oxazolone of the general formula (I) used as the starting material in the present process include 2-methyl-4-benzylidene-5-oxazolone, 2-phenyl-4-benzylidene-5-oxazolone, 2-methyl-4-(p-methylbenzylidene)-5-oxazolone, 2-phenyl-4-(p-methylbenzylidene)-5-oxazolone, 2-methyl-4-(p-ethylbenzylidene)-5-oxazolone, 2-phenyl-4-(p-iso-propylbenzylidene)-5-oxazolone, 2-methyl-4-(p-n-butylbenzylidene)-5-oxazolone, 2-methyl-4-(p-methoxybenzylidene)-5-oxazolone, 2-phenyl-4-(p-methoxybenzylidene)-5-oxazol
- the first step of the process of the present invention in which an ⁇ -acylaminocinnamic acid is produced through hydrolysis of a 2-substituted-4-(substituted)-benzylidene-5-oxazolone, comprises treating this starting material present in an aqueous medium in a state of suspension or solution by adding thereto an alkali such as the hydroxide, oxide or carbonate of an alkali or alkaline earth metal in amount in excess of its stoichiometriciequirement, thereby producing a corresponding ⁇ -acylaminocinnamic acid easily.
- an alkali such as the hydroxide, oxide or carbonate of an alkali or alkaline earth metal
- the amount of water used is one part by weight or more, or preferably two parts by weight or more from an operational standpoint, per one part by weight of the 2-substituted-4-(substituted) benzylidene-5-oxazolone starting material.
- the temperature and time duration applied in the hydrolysis are 0 - 1000C and 0.5 - 20 hours, or preferably 20 - 80°C and 1 - 15 hours, respectively.
- An aqueous solution of an alkali or alkaline earth metal salt of an ⁇ -acylaminocinnamic acid is obtained in the above manner.
- the acyloxy group will also be hydrolyzed to form a hydroxyl group-substituted ⁇ -acylaminocinnamic acid.
- various water-miscible organic solvents for example, methanol, ethanol, isopropanol, acetone, dioxane, tetrahydrofuran or the like, may be used jointly without raising any especial problems.
- the hydrolysis reaction proceeds under mild conditions even in an aqueous medium.
- the reaction solution containing an alkaline salt of an oC-acylaminocinnamic acid resulting from the foregoing first step is adjusted in pH to 5 - 9 and thereafter it is subjected to catalytic reduction in the presence of a palladium or platinum reducing catalyst to produce an N-acylphenylalanine.
- the said reaction solution is neutralized with an acid to adjust its pH in the range of 5 - 9 or preferably 5.5 - 8.5 and subsequently exposed to a reducing catalyst so as to be subjected to catalytic reduction.
- an acid to adjust its pH in the range of 5 - 9 or preferably 5.5 - 8.5 and subsequently exposed to a reducing catalyst so as to be subjected to catalytic reduction.
- hydrochloric and sulfuric acids are frequently used for the pH adjustment, there may also be used, as a matter of course, other mineral acids or organic acids such as acetic acid and p-toluenesulfonic acid.
- the pH of the reaction solution should exceed 9 during the reduction period, the catalytic activity of the recovered catalyst will, as pointed out previously, be lowered or lost through its repeated use, and even in the case of using a fresh catalyst, the reaction time duration will tend to be prolonged as opposed to the reduction carried out in the pH range of 5 to 9. Further, if the pH should be below 5, the solubility of the N-acylaminocinnamic acid will be decreased and the reduction will have to be carried out in a state of suspension so that the time taken for completion of the reaction will be prolonged unfavourably.
- any type of noble metal catalyst of the palladium or platinum series can be used as the reducing catalyst so long as it makes up a heterogenous catalytic system to the reaction solution.
- specific examples of such catalysts may include palladium-carbon, palladium black, colloidal palladium, palladium-barium sulfate, palladium-alumina, platinum oxide, platinum-carbon or platinum-silica gel.
- the catalyst used in practising the present invention is not limited to these particular, exemplary catalyst, however.
- the amount of the catalyst to be used is generally 0.1% by weight or more based on the weight of the starting material,-2-substituted-4-(substituted)-benzylidene-5-oxazolone.
- the catalyst used, the shorter will be the time required for the reduction. However, from economical and operational points of view, it is preferred to use the catalyst in an amount of 30% by weight or less. More favourably, it is recommended to use it in an amount in the range of 0.5 - 10% by weight.
- the temperature and the duration of the reduction depend more or less on the amount of the catalyst used but generally lie in the ranges of 0 - 100 0 C and 0.5 - 30 hours, respectively.
- the reduction may be effected either at atmospheric pressure or under pressure.
- N-acylphenylalanines are generally dissolved in the reaction solution after completion of the reaction, it is possible, as required, to isolate the N-acylphenylalanines from the reaction solution by filtering and removing the catalyst while the reaction solution is hot and thereafter acidifying the filtrate with an acid such as hydrochloric acid.
- the catalyst thus-recovered can be used repeatedly, maintaining its original activity to effect the reduction without any further treatment and without any observed lowering in its catalytic activity.
- the gas phase in the vessel was purged with nitrogen and then with hydrogen and thereafter the vessel's contents were subjected to catalytic reduction at 40 - 45°C under atmospheric pressure.
- the reaction time was approximately 90 minutes until hydrogen absorption was completed. During this time period, it was observed that one mole of hydrogen was absorbed to one mole of 2-methyl-4-benzylidene-5-oxazolone.
- the gas phase in the vessel was purged with nitrogen after completion of the reaction and thereafter the catalyst was filtered and washed with a small amount of water.
- the filtrate and the washings were combined and concentrated hydrochloric acid was added thereto at 30 - 35°C to adjust pH of the resultant mixture to 1.
- the mixture was then cooled to 0 - 5°C, The resulting crystals were separated by filtering, were washed with cold water and dried to obtain 9.96 g of N-acetylphenylalanine as a white crystal. Its yield was 96.1% based on the 2-methyl-4-benzylidene-5-oxazolone, and its melting point was 150.5 - 151°C.
- reaction mixture in the vessel was subjected to catalytic reduction at 40 - 45°C under atmospheric pressure. The time required for the reduction was approximately four hours. After completion of the reduction, the reaction mixture was treated in the same manner as in Example 1 to recover the catalyst and obtain 9.91 g of N-acetylphenylalanine as a white crystal. Its melting point was 149.5 - 150.5 0 C .
- Example 2 Each example was effected in the same manner as in Example 1 except that the pH of the solution during the reduction was changed. Results are shown in Table 2. Each catalyst recovered in these two experiments was used repeatedly three times under the same respective conditions. The time durations required for the reduction of these repetitions were practically the same as that resulted when a fresh catalyst was used,
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
Description
- This invention relates to a process for producing substituted or unsubstituted N-acylphenylalanines.
- N-acylphenylalanines are important compounds as precursors of phenylalanines. In particular, unsubstituted N-acylphenylalanines are categorized as essential amino acids and are important compounds as precursors of L-phenylalanine which has come to be rapidly used as a starting material of an artificial sweetner "Aspartame". For example, N-acetylphenylalanine readily undergoes asymmetric hydrolysis by the action of an enzyme acylase to form L-phenylalanine.
- Conventionally, N-acrylphenylalanines have generally been produced by the reduction of either 2-substituted-4-(substituted) benzylidene-5-oxazolones, which are produced relatively easily by a condensation reaction of an N-acylglycine and a benzaldehyde, or α-acylaminocinnamic acids which are hydrolysis products of said oxazolones. h
- Although various processes have hitherto been proposed for effecting the reduction, it is practical in an industrial sense to carry out the reduction catalytically in the presence of a heterogeneous reducing catalyst. For example, in accordance with the method of T. Okuda and Y. Fugii (Bull. Chem. Soc. (Japan), 30, 698 (1957)), a substituted or unsubstituted 2-methyl-4-benzylidene-5-oxazolone is reduced catalytically in an alkaline solution under a pressure of 40 - 70 kg/cm2 using Raney nickel as a catalyst to produce an N-acetylphenylalanine. As an example of using a heterogeneous catalyst of noble metal, there is disclosed a method by R.M. Herbst and D. Shemin (Organic Synthesis, Coll. Vol. 2, p491) wherein α-acetylaminocinnamic acid is reduced catalytically in acetic acid under atmospheric pressure using platinum oxide as a catalyst to produce N-acetylphenylalanine.
- However, since the former method carries out the reduction under a high pressure, restrictions are imposed on the apparatus that is used in effecting the method industrially. Moreover, the Raney nickel is used in a relatively large amount and thus raises environmental problems in its disposal. The prior method which uses acetic acid as a solvent is accompanied by drawbacks, e.g. that its operation is complicated because the solvent has to be concentrated or distilled upon isolation of the product after the reduction.
- Recently, noble metals such as palladium or platinum have also come to be used frequently on an industrial scale as catalysts for use in catalytic reduction. This is because these catalysts are effective in relatively small amounts, are recovered easily because they are heterogeneous to various solvents, and eliminate environmental problems caused by disposal because they are regenerative. They are extremely expensive, however. These expensive noble metal catalysts are generally used repeatedly in industry by way of their recovery after completion of reaction.
- The present inventors have hydrolyzed 2-methyl-4-benzylidene-5-oxazolone with alkali in water and reduced catalytically the resultant of-acetylamino- cinnamic acid, without isolating it from the reaction solution, by adding a palladium or platinum reducing catalyst thereto to prepare N-acetylphenylalanine. It was then found that the catalyst recovered by filtration after the reduction was lowered in catalytic activity through use, thus requiring considerably longer times in effecting subsequent reductions compared with reductions performed with fresh catalyst. Finally, the noble metal catalyst lost its activity almost completely after several repeated uses thereof. The same situation occured when other 2-substituted-4-(substituted) benzylidene-5-oxazolones were used. Further, it was also found that a catalyst whose activity had been lowered or lost could not be restored as to its catalytic activity even by washing it with an organic solvent, such as alcohol, or with an acid such as dilute hydrochloric acid and thus its catalytic activity was irreversibly degraded.
- On the basis of these experimental facts, the present inventors have made an intensive effort to establish a process for the preparation of N-acylphenylalanines from 2-substituted-4-(substituted) benzylidene-5-oxazolones wherein a reduction catalyst could be used efficiently and repeatedly without its catalytic activity being lowered or lost during the reduction. As a result of their work, it was found that the pH of the reaction solution during the reduction was closely related to the activity of the catalyst and was responsible for the irreversible decrease in activity of the recovered catalyst, thus leading to the completion of the present invention.
- Accordingly, the present invention provides a process for producing N-acylphenylalanines represented by the general formula (II):
- In performing the process of the present invention, the time period required for the reduction can be remarkably shortened compared with the time required for reduction in an aqueous, strong alkaline solution. Moreover, there is such a great advantage in the present process that the catalyst recovered through filtration after the reduction can be used repeatedly without any additional treatment and without any observed decrease in its catalytic activity. A reduction using the catalyst recovered from a previous reduction may proceed at practically the same rate as in the case of a reduction performed using fresh catalyst. Further, in the process of the present invention, the starting material, 2-substituted -4-(substituted) benzylidene-5-oxazolone, is hydrolyzed with alkali to produce a substituted or unsubstituted N-acylaminocinnamic acid which is subsequently and continuously subjected to the reduction, that is to say without being isolated from the reaction mixture. Accordingly, the present process has advantages over a process wherein a N-acylaminocinnamic acid is reduced after it has been isolated from the reaction system; the advantages include the benelit-of process simplification and surprisingly improved overall yield.
- If R1 and R (and correspondingly R3 and R ) are univalent, they can be attached to any unoccupied position on the benzylidene ring. If R1 and R 2 (and R 3 and R 4) are combined as the divalent methylenedioxy group, however, this group attaches to two adjoining positions of the benzylidene ring.
- The invention is now explained in more detail in the following non-limitative description of a preferred mode of carrying out the process.
- The process of the present invention comprises two steps consisting of (A) treating a 2-substituted-4-(substituted) benzylidene-5-oxazolone represented by the general formula (I) with alkali to form a substituted or unsubstituted α-acylaminocinnamic acid and (B) reducing catalytically the resultant α-acylaminocinnamic acid without isolating it from the reaction system.
- Specific examples of the 2-substituted-4-(substituted)benzylidene-5-oxazolone of the general formula (I) used as the starting material in the present process include 2-methyl-4-benzylidene-5-oxazolone, 2-phenyl-4-benzylidene-5-oxazolone, 2-methyl-4-(p-methylbenzylidene)-5-oxazolone, 2-phenyl-4-(p-methylbenzylidene)-5-oxazolone, 2-methyl-4-(p-ethylbenzylidene)-5-oxazolone, 2-phenyl-4-(p-iso-propylbenzylidene)-5-oxazolone, 2-methyl-4-(p-n-butylbenzylidene)-5-oxazolone, 2-methyl-4-(p-methoxybenzylidene)-5-oxazolone, 2-phenyl-4-(p-methoxybenzylidene)-5-oxazolone, 2-methyl-4-(3,4-dimethoxybenzylidene)-5-oxazolone, 2-methyl-4-(2,3-dimethoxybenzylidene)-5-oxazolone, 2-phenyl-4-(2,4-dimethoxybenzylidene)-5-oxazolone, 2-methyl-4-(3,5-dimethoxybenzylidene)-5-oxazolone, 2-methyl-4-(p-ethoxybenzylidene)-5-oxazolone, 2-methyl-4-(3,4-diethoxybenzylidene)-5-oxazolone, 2-phenyl-4-(p-n-propoxybenzylidene)-5-oxazolone, 2-methyl-4-(p-n-butoxybenzylidene)-5-oxazolone, 2-methyl-4-(p-chlorobenzylidene)-5-oxazolone, 2-phenyl-4-(p-chorobenzylidene)-5-oxazolone, 2-methyl-4-(3,4-dichlorobenzylidene)-5-oxazolone, 2-phenyl-4-(3,4-dichlorobenzylidene)-5-oxazolone, 2-methyl-4-(m-phenoxybenzylidene)-5-oxazolone, 2-phenyl-4-(m-phenoxybenzylidene)-5-oxazolone, 2-methyl-4-(p-acetoxybenzylidene)-5-oxazolone, 2-phenyl-4-(p-acetoxybenzylidene)-5-oxazolone, 2-methyl-4-(3,4-diacetoxybenzylidene)-5-oxazolone, 2-phenyl-4-(3,4-diacetoxybenzylidene)-5-oxazolone, 2-methyl-4-(3,4-methylenedioxybenzylidene)-5-oxazolone or 2-phenyl-4-(3,4-methylenedioxybenzylidene)-5-oxazolone. These starting materials can easily be produced by the Elrenmeyer method in which N-acetylglycine or N-benzoylglycine (hippuric acid) is condensed with a substituted or unsubstituted benzaldehyde in acetic anhydride in the presence of anhydrous sodium acetate. Another method involves treating a p-phenylserine in acetic anhydride in the presence of a base (Japanese Patent Application Laid-Open No. 32753/1985).
- The first step of the process of the present invention, in which an α-acylaminocinnamic acid is produced through hydrolysis of a 2-substituted-4-(substituted)-benzylidene-5-oxazolone, comprises treating this starting material present in an aqueous medium in a state of suspension or solution by adding thereto an alkali such as the hydroxide, oxide or carbonate of an alkali or alkaline earth metal in amount in excess of its stoichiometriciequirement, thereby producing a corresponding α-acylaminocinnamic acid easily. The amount of water used is one part by weight or more, or preferably two parts by weight or more from an operational standpoint, per one part by weight of the 2-substituted-4-(substituted) benzylidene-5-oxazolone starting material. The temperature and time duration applied in the hydrolysis are 0 - 1000C and 0.5 - 20 hours, or preferably 20 - 80°C and 1 - 15 hours, respectively. An aqueous solution of an alkali or alkaline earth metal salt of an α-acylaminocinnamic acid is obtained in the above manner. However, in a case where an acyloxy group-substituted oxazolone is used as the starting material, the acyloxy group will also be hydrolyzed to form a hydroxyl group-substituted α-acylaminocinnamic acid. In the hydrolysis of 2-substituted-4-(substituted) benzylidene-5-oxazolones, various water-miscible organic solvents, for example, methanol, ethanol, isopropanol, acetone, dioxane, tetrahydrofuran or the like, may be used jointly without raising any especial problems. However, the hydrolysis reaction proceeds under mild conditions even in an aqueous medium. It may sometimes be necessary to distill or remove such an organic solvent in the isolation of the intended compound of N-acrylphenyl- alanine after completion of the subsequent catalytic reduction, so that the post-reaction treatment is made complicated. From this point of view, it is not usually preferred to employ an organic solvent in the aqueous medium.
- In the second step of the process of the present invention, the reaction solution containing an alkaline salt of an oC-acylaminocinnamic acid resulting from the foregoing first step is adjusted in pH to 5 - 9 and thereafter it is subjected to catalytic reduction in the presence of a palladium or platinum reducing catalyst to produce an N-acylphenylalanine.
- For effecting the catalytic reduction of this step, the said reaction solution is neutralized with an acid to adjust its pH in the range of 5 - 9 or preferably 5.5 - 8.5 and subsequently exposed to a reducing catalyst so as to be subjected to catalytic reduction. Although hydrochloric and sulfuric acids are frequently used for the pH adjustment, there may also be used, as a matter of course, other mineral acids or organic acids such as acetic acid and p-toluenesulfonic acid. If the pH of the reaction solution should exceed 9 during the reduction period, the catalytic activity of the recovered catalyst will, as pointed out previously, be lowered or lost through its repeated use, and even in the case of using a fresh catalyst, the reaction time duration will tend to be prolonged as opposed to the reduction carried out in the pH range of 5 to 9. Further, if the pH should be below 5, the solubility of the N-acylaminocinnamic acid will be decreased and the reduction will have to be carried out in a state of suspension so that the time taken for completion of the reaction will be prolonged unfavourably.
- Any type of noble metal catalyst of the palladium or platinum series can be used as the reducing catalyst so long as it makes up a heterogenous catalytic system to the reaction solution. Specific examples of such catalysts may include palladium-carbon, palladium black, colloidal palladium, palladium-barium sulfate, palladium-alumina, platinum oxide, platinum-carbon or platinum-silica gel. The catalyst used in practising the present invention is not limited to these particular, exemplary catalyst, however. The amount of the catalyst to be used is generally 0.1% by weight or more based on the weight of the starting material,-2-substituted-4-(substituted)-benzylidene-5-oxazolone. The more catalyst used, the shorter will be the time required for the reduction. However, from economical and operational points of view, it is preferred to use the catalyst in an amount of 30% by weight or less. More favourably, it is recommended to use it in an amount in the range of 0.5 - 10% by weight.
- The temperature and the duration of the reduction depend more or less on the amount of the catalyst used but generally lie in the ranges of 0 - 1000 C and 0.5 - 30 hours, respectively. The reduction may be effected either at atmospheric pressure or under pressure.
- Since N-acylphenylalanines are generally dissolved in the reaction solution after completion of the reaction, it is possible, as required, to isolate the N-acylphenylalanines from the reaction solution by filtering and removing the catalyst while the reaction solution is hot and thereafter acidifying the filtrate with an acid such as hydrochloric acid. The catalyst thus-recovered can be used repeatedly, maintaining its original activity to effect the reduction without any further treatment and without any observed lowering in its catalytic activity.
- The present invention will be described more specifically with reference to the following non-limiting examples.
- In a 100-ml tightly-sealed glass vessel were charged 9.36 g of 2-methyl-4-benzylidene-5-oxazolone and 30 ml of water. Thereafter, 5.3 g of 45% sodium hydroxide solution was added thereto and the resulting mixture was stirred at 40 - 45°C for 2 hours. The 2-methyl-4-benzylidene-5-oxazolone was hydrolyzed to form an aqueous homogeneous solution of sodium α-acetylaminocinnamate. Then, concentrated hydrochloric acid was added to the solution to adjust its pH to 7.2, and subsequently 0.2 g of 5%-palladium-carbon was added thereto. The gas phase in the vessel was purged with nitrogen and then with hydrogen and thereafter the vessel's contents were subjected to catalytic reduction at 40 - 45°C under atmospheric pressure. The reaction time was approximately 90 minutes until hydrogen absorption was completed. During this time period, it was observed that one mole of hydrogen was absorbed to one mole of 2-methyl-4-benzylidene-5-oxazolone.
- The gas phase in the vessel was purged with nitrogen after completion of the reaction and thereafter the catalyst was filtered and washed with a small amount of water. The filtrate and the washings were combined and concentrated hydrochloric acid was added thereto at 30 - 35°C to adjust pH of the resultant mixture to 1. The mixture was then cooled to 0 - 5°C, The resulting crystals were separated by filtering, were washed with cold water and dried to obtain 9.96 g of N-acetylphenylalanine as a white crystal. Its yield was 96.1% based on the 2-methyl-4-benzylidene-5-oxazolone, and its melting point was 150.5 - 151°C.
- In the same manner as in Example 1, 2-methyl-4-benzylidene-5-oxazolone was treated with alkali to obtain an aqueous solution of sodium N-acetylamino- cinnamate which was then subjected to reduction, after adjusting its pH with concentrated hydrochloric acid to 7.2, using the palladium-carbon catalyst recovered in Example 1 without any further treatment. The catalyst was used repeatedly five times for effecting the reduction. Results are shown in Table 1. In each of the repeated experiments, the reduction was completed in 95 - 105 minutes. This signifies in comparison with Example 1 that each reduction time was not, in practical terms, affected by the repeated use of catalyst.
- In a 100-ml tightly-sealed glass vessel were charged 9.36 g of 2-methyl-4-benzylidene-5-oxazolone and 30 ml of water. Then, 5.3 g of 45% sodium hydroxide solution was added thereto and the resulting mixture was stirred at 40 - 450C for two hours. The 2-methyl-4-benzylidene-5-oxazolone was hydrolyzed to form an aqueous homogeneous solution of sodium α-acetylaminocinnamate. The solution had a pH in excess of 12. 0.2 g of 5%-palladium-carbon was then added to the solution. After the gas phase in the vessel was purged with nitrogen and then with hydrogen, the reaction mixture in the vessel was subjected to catalytic reduction at 40 - 45°C under atmospheric pressure. The time required for the reduction was approximately four hours. After completion of the reduction, the reaction mixture was treated in the same manner as in Example 1 to recover the catalyst and obtain 9.91 g of N-acetylphenylalanine as a white crystal. Its melting point was 149.5 - 150.50 C.
- Procedures of Comparative Example 1 were repeated to effect the reaction except for the repeated use of the catalyst recovered in Comparative Example 1. The time durations required for the reduction were 6.5 hours and 10 hours for the first and second repeated uses, respectively. In the third repeated use, hydrogen absorption was interrupted during the reduction.
- Each example was effected in the same manner as in Example 1 except that the pH of the solution during the reduction was changed. Results are shown in Table 2. Each catalyst recovered in these two experiments was used repeatedly three times under the same respective conditions. The time durations required for the reduction of these repetitions were practically the same as that resulted when a fresh catalyst was used,
- In 100-ml tightly-sealed glass vessel were charged 9.36 g of 2-methyl-4-benzylidene-5-oxazolone and 40 ml of water. 4.15 g of potassium carbonate was then added thereto and the resulting mixture was stirred at 40 - 450C for two hours. Concentrated hydrochloric acid was added to the resulting solution to adjust its pH to 6.8 and 0.2 g of 5%- palladium-carbon was added thereto. The gas phase in the vessel was purged with nitrogen and then with hydrogen, and thereafter the reaction mixture in the vessel was subjected to catalytic reduction at 40 - 45°C under atmospheric pressure. The reaction time during which hydrogen absorption was completed was 100 minutes. It was observed that one mole of hydrogen was absorbed to one mole of 2-methyl-4-benzylidene-5-oxazolone during this period. After the gas phase in the vessel was purged with nitrogen upon completion of the reaction, the catalyst was filtered and washed with a small amount of water. The filtrate and the washings were combined, and concentrated hydrochloric acid was added at a temperature lower than 30°C to adjust the pH of the resulting mixture to 1. The mixture was cooled to 0 - 5°C. Crystals formed and were separated by filtration, were washed with cold water and dried to obtain 9.81 g of N-acetylphenylalanine having a melting point of 150 - 151°C as a white crystal. The yield was 94.7%.
- Using the recovered catalyst repeatedly, experiments were carried out three times under the same conditions as described above. In each of the experiments, the time duration required for the reduction was in the range of 95 - 110 minutes which was practically the same as in the case of using a fresh catalyst.
- 0.05 mole of each of various 2-substituted-4-(substituted) benzylidene-5-oxazolones was suspended in 40 - 100 ml of water and 5.3 g of 45% sodium hydroxide solution was added thereto to hydrolyze it at 40 - 80°C for 1 - 3 hours, thereby forming a corresponding d-acylaminocinnamic acid. Then concentrated hydrochloric acid was added to the resultant aqueous solution to adjust its pH to 5.5 - 8.5. The resultant solution was charged into a tightly-sealed glass vessel. 5%- palladium-carbon was added thereto and the gas phase in the vessel was purged with nitrogen and with hydrogen. Thereafter, the reaction mixture was subjected to catalytic reduction under atmospheric pressure. Procedures of Example 1 were repeated in the isolation of each of N-acylphenylalanines resulted from the reduction. Results are shown in Table 3.
Claims (9)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP59069999A JPS60215657A (en) | 1984-04-10 | 1984-04-10 | Preparation of n-acylphenylalanine |
JP69999/84 | 1984-04-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0161796A1 true EP0161796A1 (en) | 1985-11-21 |
EP0161796B1 EP0161796B1 (en) | 1989-03-08 |
Family
ID=13418875
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP85302503A Expired EP0161796B1 (en) | 1984-04-10 | 1985-04-09 | Process for producing n-acylphenylalanines |
Country Status (9)
Country | Link |
---|---|
US (1) | US4612388A (en) |
EP (1) | EP0161796B1 (en) |
JP (1) | JPS60215657A (en) |
KR (1) | KR870000368B1 (en) |
AU (1) | AU558388B2 (en) |
CA (1) | CA1228364A (en) |
DE (1) | DE3568573D1 (en) |
ES (1) | ES542019A0 (en) |
MX (1) | MX162421A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2591070A1 (en) * | 1985-12-06 | 1987-06-12 | Budapesti Vegyimuevek | NOVEL NON-SATURATED AZLACTONE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PESTICIDE COMPOSITIONS COMPRISING SAME |
GB2188047A (en) * | 1986-03-04 | 1987-09-23 | Toyo Jozo Kk | Aldose reductase inhibitors |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63502112A (en) * | 1986-01-03 | 1988-08-18 | コンソリデイテツド・フアーマシユーテイカルズ・リミテツド | Melphalan derivative |
DE3736861A1 (en) * | 1987-10-30 | 1989-05-11 | Hoechst Ag | METHOD FOR PRODUCING N-ACETYLPHENYLALANINE |
IT1226903B (en) * | 1988-07-12 | 1991-02-21 | Mini Ricerca Scient Tecnolog | PROCESS FOR THE SYNTHESIS OF OPTICALLY ACTIVE AMINO ACIDS |
BR9306656A (en) * | 1992-06-30 | 1998-12-08 | Legomer Partners Lp | Mimetic composition of nucleotide peptide and substrate compound carbohydrate and process for synthesizing a compound |
US5670480A (en) * | 1994-01-05 | 1997-09-23 | Arqule, Inc. | Method of making polymers having specific properties |
TW200624151A (en) * | 2004-11-12 | 2006-07-16 | Monsanto Technology Llc | Recovery of noble metals from aqueous process streams |
CN101684077B (en) | 2008-09-24 | 2013-01-02 | 浙江九洲药业股份有限公司 | Method for preparing N-acyl diphenylalanine |
CA2772681C (en) * | 2009-09-23 | 2017-01-03 | Zhejiang Jiuzhou Pharmaceutical Co., Ltd. | Process for manufacture of n-acylbphenyl alanine |
CN111518049B (en) * | 2019-02-01 | 2024-05-03 | 鲁南制药集团股份有限公司 | MAGL inhibitor, preparation method and application |
CN111518048B (en) * | 2019-02-01 | 2024-04-30 | 鲁南制药集团股份有限公司 | MAGL inhibitors, methods of preparation and uses |
CN111518047B (en) * | 2019-02-01 | 2024-05-24 | 鲁南制药集团股份有限公司 | MAGL inhibitor and preparation method and application thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3838008A (en) * | 1970-01-19 | 1974-09-24 | Astra Laekemedel Ab | Stereoselective preparation of l-dopa and l-m-tyrosine and novel compounds |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2678313A (en) * | 1954-05-11 | Stable molecular compounds of | ||
US3085111A (en) * | 1957-03-19 | 1963-04-09 | Warner Lambert Pharmaceutical | Process for preparing 3-nitrobenzaldehyde ethers |
CH441362A (en) * | 1963-12-24 | 1967-08-15 | Hoffmann La Roche | Process for the preparation of phenylalanine derivatives |
US3544623A (en) * | 1966-05-18 | 1970-12-01 | Warner Lambert Pharmaceutical | 3-isopropyltyrosine |
US4261919A (en) * | 1968-09-09 | 1981-04-14 | Monsanto Company | Catalytic asymmetric hydrogenation |
US4508921A (en) * | 1984-06-28 | 1985-04-02 | Merck & Co., Inc. | Process for preparation of alpha-alkyl amino acids |
-
1984
- 1984-04-10 JP JP59069999A patent/JPS60215657A/en active Granted
-
1985
- 1985-04-03 AU AU40787/85A patent/AU558388B2/en not_active Ceased
- 1985-04-03 US US06/719,300 patent/US4612388A/en not_active Expired - Fee Related
- 1985-04-08 ES ES542019A patent/ES542019A0/en active Granted
- 1985-04-08 MX MX204875A patent/MX162421A/en unknown
- 1985-04-09 EP EP85302503A patent/EP0161796B1/en not_active Expired
- 1985-04-09 CA CA000478605A patent/CA1228364A/en not_active Expired
- 1985-04-09 DE DE8585302503T patent/DE3568573D1/en not_active Expired
- 1985-04-10 KR KR1019850002413A patent/KR870000368B1/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3838008A (en) * | 1970-01-19 | 1974-09-24 | Astra Laekemedel Ab | Stereoselective preparation of l-dopa and l-m-tyrosine and novel compounds |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2591070A1 (en) * | 1985-12-06 | 1987-06-12 | Budapesti Vegyimuevek | NOVEL NON-SATURATED AZLACTONE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PESTICIDE COMPOSITIONS COMPRISING SAME |
GB2188047A (en) * | 1986-03-04 | 1987-09-23 | Toyo Jozo Kk | Aldose reductase inhibitors |
US4749571A (en) * | 1986-03-04 | 1988-06-07 | Toyo Jozo Co., Ltd. | Physiologically-active novel substance "Aldostatin" and production method thereof |
GB2188047B (en) * | 1986-03-04 | 1989-12-28 | Toyo Jozo Kk | Aldose reductase inhibitor |
Also Published As
Publication number | Publication date |
---|---|
JPS60215657A (en) | 1985-10-29 |
CA1228364A (en) | 1987-10-20 |
EP0161796B1 (en) | 1989-03-08 |
MX162421A (en) | 1991-05-09 |
ES8601855A1 (en) | 1985-12-01 |
DE3568573D1 (en) | 1989-04-13 |
JPH0542422B2 (en) | 1993-06-28 |
KR870000368B1 (en) | 1987-03-06 |
ES542019A0 (en) | 1985-12-01 |
AU558388B2 (en) | 1987-01-29 |
AU4078785A (en) | 1985-10-17 |
US4612388A (en) | 1986-09-16 |
KR850007795A (en) | 1985-12-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0161796B1 (en) | Process for producing n-acylphenylalanines | |
JP2839344B2 (en) | Method for producing cyclic amino acid and intermediate thereof | |
US4713454A (en) | Preparation process of (6R)-tetrahydro-L-biopterin | |
US3950405A (en) | Trans-4-aminomethylcyclohexane-1-carboxylic acid | |
US3499925A (en) | Process for the production of trans-4-aminomethylcyclohexane - 1 - carboxylic acid | |
US4005088A (en) | Process for the chemical separation of racemic modifications of α-aminocarboxylic acid derivatives, and cinchonidine salt intermediates | |
US4716246A (en) | Process for L-dopa | |
EP0190687B1 (en) | Process for preparing ethyl-alpha-(1-carboxyethyl)-amino-gamma-oxo-gamma-phenylbutyrate | |
US4994597A (en) | Method for preparing optically active 3,4-dihydroxy butyric acid derivatives | |
EP0598383B1 (en) | Process for the preparation of 5,6-diacetoxyindole | |
JPH05279325A (en) | Production of optically active 3-hydroxypyrolidine | |
JPH0971571A (en) | Optical resolving agent and production of optically active 2-piperazinecarboxylic acid derivative with the same | |
EP0339618B1 (en) | Method for preparing optically active 3,4-dihydroxy butyric acid derivatives | |
JPH08157437A (en) | Production of d-amino acid-n-(s)-alpha-alkylbenzylamide | |
US4414404A (en) | Process for producing N-acyl-D,L-phenylalanine ester | |
JPH07285934A (en) | Method for removing protecting group | |
US4113741A (en) | Method of preparing phthalide | |
JPH09143128A (en) | Production of optically active 1-phenylethylamine | |
KR100461562B1 (en) | Method for racemization of optically active phenylglycine | |
US4883900A (en) | Process for the preparation of aspartame and agents for carrying it out | |
JPH0510337B2 (en) | ||
JPH07103099B2 (en) | Process for producing optically active 3-hydroxypyrrolidine | |
JP3046383B2 (en) | Method for producing optically active indolehydroxy acids | |
JP3654050B2 (en) | Method for producing N-acetylcyclohexylglycine | |
JPH0296555A (en) | Production of 4-carboxyamidecyclohexane carboxylic acid esters |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Designated state(s): CH DE FR GB IT LI NL |
|
17P | Request for examination filed |
Effective date: 19860426 |
|
17Q | First examination report despatched |
Effective date: 19870311 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): CH DE FR GB IT LI NL |
|
ITF | It: translation for a ep patent filed | ||
REF | Corresponds to: |
Ref document number: 3568573 Country of ref document: DE Date of ref document: 19890413 |
|
ET | Fr: translation filed | ||
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed | ||
ITTA | It: last paid annual fee | ||
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 19940315 Year of fee payment: 10 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 19940331 Year of fee payment: 10 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 19940428 Year of fee payment: 10 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 19940430 Year of fee payment: 10 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 19940728 Year of fee payment: 10 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Effective date: 19950409 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Effective date: 19950430 Ref country code: CH Effective date: 19950430 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Effective date: 19951101 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 19950409 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Effective date: 19951229 |
|
NLV4 | Nl: lapsed or anulled due to non-payment of the annual fee |
Effective date: 19951101 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Effective date: 19960103 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST |